Suppose someone is given an assignment to obtain/extract propranolol (PL) from a mixture of microcrystalline cellulose (MC) and a propranolol·HCl (PL·HCl). In a sense, it will be a fractional extraction procedure where one would exploit differences in the chemical or physical nature of these two compounds. The very first difference one observes will be in their aqueous solubilities; MC is not soluble in water, but PL·HCl is. So, one can separate PL·HCl from MC by simply adding some water and filtering it. The PL·HCl will remain in solution form but MC will be separated out as precipitate. However, PL will still be in its hydrochloride form. To extract the PL, one may require a liquid-liquid extraction step. In this regard, one first needs to adjust the pH of the aqueous solution so that the HCl part can be neutralized and PL·HCl should be available as PL which could then be extracted with an organic solvent (e.g. hexane or dichloromethane). Adding some alkaline solution to PL solution will increase the pH of the solution to a much higher level, e.g. pH 12. Most of the PL will now be in undissociated form and can be extracted into the organic phase. One or two extraction repeats will transfer PL into the organic phase which may be removed by evaporation, leaving behind pure PL in its native or basic form.
On the other hand, if one is unable to increase the pH of the solution to 12, to avoid potential complications, then a lower pH may be used. The same extraction step can be used, however, one would require an increased number of extraction repeats for complete extraction of PL from the aqueous solution. The end result will be the same i.e. complete extraction of PL form in its native or basic form in the organic solvent.
It is important to note that one can also perform the above described extraction in one step (i.e. without separating MC by filtration first). In this case, adding some milder buffer having a pH around 7 to the mixture, to avoid any complications of higher pH with MC.
Now let us assume that this extraction process of PL is to occur in the intestinal tube rather than in a glass test tube as explained above. The content of the intestinal tube are at a pH, between 5 and 7, and contains multiple endogenous and exogenous compounds including PL and MC. The organic phase for test tube experiment is replaced with the lipid layers of the intestinal tube walls. When the undissociated PL comes in contact with the lipid part of the intestinal tube it will get absorbed or extracted. This process will occur almost an infinite number of times (considering the vast surface area of the intestines). Once PL, or any other drug, gets absorbed it will be transferred to the blood stream.
This process of liquid-liquid drug extraction is commonly referred to as absorption of drugs in human by passive diffusion. However, the process in both cases (in vitro vs in vivo) is almost the same, if not exactly these same. It is worth remembering that the majority of drug absorbed through GI tract occurs through a passive diffusion process.
What this means is that when someone takes a solid oral product (tablet and capsule), the drug must first comes out of the product and then to dissolve as a non-polar (undissociated) drug in the intestinal fluid. The drug does not have to be completely dissolved but to the extent that the continuous process of extraction/absorption to occur efficiently and sufficiently within the intestine.
In conclusion, drug absorption occurs as a liquid-liquid extraction process for which dissolution of the drug within the GI tract is one of the most critical steps. However, it is generally not necessary or required that the drug has to be completely dissolved at a given time for successful and efficient drug absorption. Efficient and successful drug absorption can occur by continuously replenishing the extracted/absorbed portion of the drug, as often low solubility drugs (mostly non-polar) show quite a high and efficient drug absorption.
